JP2008507519A - (S) -6- (4- (2-((3- (9H-carbazol-4-yloxy) -2-hydroxypropyl) amino) -2-methylpropyl) phenoxy) -3-pyridinecarboxamide hemisuccinate Crystalline nonstoichiometric hydrate - Google Patents

Abstract

The present invention relates to a crystalline variable hydrate of (S)-(3-pyridinecarboxamide,6-[4-[2-[[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy])-hemi-succinate, a pharmaceutical formulation containing said salt and to methods for treating obesity and/or Type 2 diabetes using said salt.

Description

（ＩＩ） Compounds of formula II useful as selective β ₃ receptor agonists, and pharmacologically acceptable salts thereof, are disclosed by Heath et al. In EP 817,627 (Heath). .

(II)

Example 126 from Heath discloses the synthesis of hemisuccinate (hereinafter referred to as “SAM Classic”) of the compound of formula II having the following structure:

  The synthesis method describes the production of an “amorphous” form of SAM Classic that “contains a trace amount of residual ethanol”. Heath described the formation of amorphous SAM Classic by solvent exchange of water and ethanol in the crystalline ethanolic solvate of SAM Classic. In particular, Heath stated, “The mixture was vacuum filtered (from a water slurry) and the filter cake was washed with water (3 × 100 ml). The solid was removed under vacuum for approximately 2 hours and then in a vacuum oven (65 ° C.). It was air-dried overnight to give the (amorphous) product as a whitish solid ". Accordingly, Heath disclosed that in the process of drying a wet cake-like material, the crystal structure of the initially isolated material (present as a wet cake) collapsed to form an amorphous SAM Classic. To do.

  For formulation processing, imperfect crystalline materials, particularly amorphous materials, are generally less desirable than highly crystalline materials. In addition, it is generally undesirable to prepare a medicament containing a substantial amount of an organic solvent because the potential solvent toxicity and the ability of the medicament to these recipients vary as a function of the solvent. Amorphous SAM Classic prepared by the procedure taught in '474 can be used as a formulation, but it can be reproducibly and efficiently prepared on an industrial scale and is in the crystal structure It is highly desirable and advantageous to find a stable crystalline form of SAM Classic that does not contain an amount of organic solvent.

  Surprisingly, according to the present invention, SAM Classic crystalline hydrates can be reproducibly produced, isolated and prepared on an industrial scale, are sufficiently stable for use in oral formulations, and high It has been discovered that it can be produced and isolated in a crystalline state.

  The present invention relates to (S)-(3-pyridinecarboxamide, 6- [4] in which the water content of the hydrate is 6 to 11% by weight when measured at 22 ± 5 ° C. and a relative humidity of 10 to 80%. -[2-[[3- (9H-carbazol-4-yloxy) -2-hydroxypropyl] amino] -2-methylpropyl] phenoxy])-hemi-succinate crystalline non-stoichiometric hydrate . Hereinafter, this crystalline substance is referred to as “SAM Classic hydrate”.

  The present invention further provides that when using a copper radiation source (CuKα; λ = 1.54056 Angstroms) at 20-25 ° C. and 25-30% relative humidity (RH), the pattern is 2θ at 7θ. SAM Classic hydrate with X-ray diffraction patterns including peaks at 6 ± 0.1 and 8.8 ± 0.1 °.

  In another embodiment, the present invention relates to a pharmaceutical composition comprising a SAM Classic hydrate and a pharmacological carrier. In yet another embodiment, the pharmaceutical composition of the invention may be adapted for use in the treatment of obesity and / or type II diabetes.

  The present invention further relates to a method of treating obesity and / or type II diabetes comprising administering to a patient in need of these treatments an effective amount of SAM Classic hydrate.

  In addition, the present invention relates to SAM Classic hydrate for the treatment of obesity and / or type II diabetes. In yet another embodiment, the present invention relates to the use of SAM Classic hydrate for the manufacture of a medicament for the treatment of obesity and / or type II diabetes.

  For purposes of the invention claimed herein, the following terms are defined.

  The term “pharmacological” as used herein means, as an adjective, that it is not substantially harmful.

  As used herein, the term “patient” refers to non-human animals such as humans and companion animals (eg, dogs, cats, horses). A preferred patient is a human.

  As used herein, the terms “treatment” and “treat” refer to reducing, ameliorating, preventing, stopping, suppressing, the progression or severity of a pathological condition or their sequelae, as described herein. Means delay, stop, or reverse.

  The term “patient in need of these treatments” is a patient suffering from a medical diagnosis, ie, a pathological condition claimed herein, as determined by a physician, or a sequelae thereof.

  The term “effective amount” as used herein refers to the amount of SAM Classic hydrate that is capable of treating the conditions described herein.

  According to Heath, removing the water from the wet cake-like precursor by air-drying in vacuum oven for approximately 2 hours and then at 65 ° C. overnight in a vacuum oven resulted in the collapse of the crystal structure of the precursor. An amorphous SAM Classic described in Heath is obtained. Thus, when prepared using standard laboratory / manufacturing techniques described in the aforementioned references at Heath, the crystal structure of SAM Classic hydrate is not stable and the active pharmaceutical ingredient (API) It is suggested that it is not suitable for developing as. As described herein, Applicants have found an industrially suitable method for preparing and isolating SAM Classic hydrate.

SAM Classic hydrate properties SAM Classic hydrate properties using various methods including hygroscopic analysis, Karl Fischer analysis, X-ray powder diffraction (XRD) and solid state ¹³ C nuclear magnetic resonance (SSNMR). To clarify.

  The hygroscopic profile for SAM Classic hydrate reveals that SAM Classic hydrate is a non-stoichiometric hydrate. The crystal structure of SAM Classic hydrate retains approximately 6-11% moisture at 10-80% relative humidity. Hydrates are rapidly equilibrated in the atmosphere, but the water content observed by analytical techniques depends on the relative humidity when the sample is equilibrated.

The water content of the SAM Classic hydrate may be determined by a suitable Karl Fischer (KF) titration method, for example, volumetric Karl Fischer titration using the Metrohm® method. The water content by KF is determined by the quantitative reaction of iodine and sulfur dioxide with water in the presence of an alcohol and an organic base such as pyridine. The amount of water is quantified by endpoint determination using an appropriately calibrated titration standard.
Method conditions: standard purified water; titration-Hydranal Composite 2K pyridine-free reagent or AquaStar Comp2 pyridine-free reagent or equivalent (2 mg / mL); volumetric flow rate-5 ml / min; stirrer speed-no bubbles in titration vessel Maximum speed.
Procedure: Transfer an aliquot of sample (200 mg or more) to the titration vessel. Prior to analysis, the sample is completely dissolved in absolute methanol. Perform a first titration. A second titration is performed using approximately the same amount of SAM Classic hydrate used in the first titration. The average of these titration results is calculated.
Calculation: Water (%) = [([T] × V _titration ) / Wt _sample ] × 100%
[T] = titration concentration V _titration = titration used for titration Wt _sample = sample weight (mg)

  X-ray powder diffraction patterns are obtained with a Siemens D5000 X-ray powder diffractometer equipped with a CuKα source (λ = 1.54056 Å) and operating at 50 kV and 40 mA with a Kevex solid state Si (Li) detector. Using a 1 mm divergence and light receiving slit and a 0.1 mm detection slit, the sample is scanned at 0.02 ° per step size for 3.0 seconds and 2θ at 4-40 °. For analysis, sprinkle the dry powder on a low background sample holder at 20-25 ° C. and 25-30% relative humidity (RH).

A representative XRD trace of SAM Classic hydrate is shown in FIG. The XRD pattern shows a highly crystalline material characterized by sharp peaks and a flat baseline. Table 1 shows the I / _Io data corresponding to the position of the 2θ angle peak and all peaks having an intensity of 10% or more of the maximum peak. All data in Table 1 are shown with an accuracy of ± 0.1 ° at 2θ.

  It is well known in the crystallography art that for any crystal form, the relative intensity of the diffraction peak varies with the preferred orientation caused by factors such as crystal morphology. When the effect of selection orientation is present, the intensity of the peak changes, but the position of the polymorphic characteristic peak remains unchanged. See, for example, US Pharmacopeia # 23, International Pharmacopeia # 18, pages 1843-1844, 1995. Furthermore, it is well known in the crystallography art that the position of the angle peak varies slightly for any crystal form. For example, the position of the peak changes due to a change in temperature or humidity at which the sample is analyzed or a sample displacement. In this case, since these potential changes can be taken into account in the fluctuation of the peak position of ± 0.1 ° at 2θ, there is no problem in clearly identifying the SAM Classic hydrate.

  When using a copper radiation source (CuKα; λ = 1.54056 Angstrom) and obtaining a pattern at 20-25 ° C. and 25-30% relative humidity (RH) based on peak intensity and peak position, 2θ SAM Classic hydrates may be identified by the presence of peaks at 7.6 ± 0.1 and 8.8 ± 0.1 °. Further, when the pattern was obtained as described above, the presence of SAM Classic hydrate may be demonstrated by peaks at 13.1 ± 0.1 and 15.5 ± 0.1 ° at 2θ, and 8 at 2θ. 0.0 ± 0.1, 11.0 ± 0.1, 13.3 ± 0.1, 13.8 ± 0.1 and 15.3 ± 0.1 ° by the presence of SAM Classic hydrate You may prove existence.

¹³ C SSNMR analysis was performed on a Varian Unity Inova 400 MHz spectrometer operated at a carbon frequency of 100.578 MHz using strong proton decoupling, cross polarization (CP) and 7.0 kHz magic angle rotation (MAS). Is called. The parameters obtained are 90 ° proton r. f. The pulse width is 4.0 μs, the contact time is 1.5 ms, the pulse repetition time is 5 s, the spectral width is 50 kHz, and the acquisition time is 50 ms. Chemical shifts expressed as parts per million (ppm) refer to the methyl group of hexamethylbenzene (δ = 17.3 ppm) by sample substitution. The magic angle is the sideband of the ⁷⁹ Br signal of KBr, as described by Freee and Maciel (Frye J. S. and Maciel G. E., J. Magn. Reson., 1982, 48, 125). Optimized and adjusted.

SAM Classic hydrate is 33% R.D. before data collection. H. May be identified by the presence of isotropic peaks at 59.8 ± 0.1, 111.4 ± 0.1 and 151.4 ± 0.1 ppm. In addition, 33% R.D. H. SAM Classic hydrates are 99.2 ± 0.1, 102.4 ± 0.1, 134.9 ± 0.1, 146.9 ± 0.1 and 149. Characterized by solid state ¹³ C nuclear magnetic resonance spectra at 2 ± 0.1 ppm.

The amount (weight percentage) of a solvent such as methanol, ethanol or ethyl acetate present in the crystalline material may be measured by headspace gas chromatography with flame ionization detection. A sample of crystalline solid (50 mg) is weighed in a headspace vial and dissolved in 2 mL of dimethyl sulfoxide. Vials are incubated at 80 ° C. for 5 minutes and then analyzed using a DB624 column (30 meters, 0.53 mm id, 3 micron film thickness). The target solvent is eluted while maintaining the column temperature at 40 ° C. for 10 minutes, and the oven temperature is raised to 240 ° C. to elute the solvent peak of the sample. In GC, helium is used as a carrier gas at a flow rate of approximately 5 ml / min. The inlet temperature is set at 220 ° C. to a 1: 5 split ratio and 1 mL injection volume. The detector temperature is 250 ° C. The amount of solvent is determined relative to a solvent standard prepared to a known concentration. A linear least squares calibration curve is generated using standard concentrations (mg / mL) and standard peak areas. The solvent peak area during sample injection is compared to a calibration curve to determine the solvent concentration for each sample injection. The proportion of solvent is calculated using the following formula:
Solvent (%) = (Solvent amount (mg / mL) (2.0 mL) × 100
Sample (mg)

Reverse phase HPLC with UV detection may be used to measure the abundance (weight percentage) of chemical impurities in the crystalline material. A sample of crystalline solid (approximately 10 mg) is weighed into a 25 ml volumetric flask and diluted with a methanol / water 70/30 (v / v) mixture. This aliquot of the solution is assayed using a Zorbax SB-phenyl column (25 cm × 4.6 mm ID 5 micron particles). The injection volume is 5 microliters at an autosampler temperature of 5 ° C. The detector wavelength is 240 nm and the column flow rate is 1.0 ml / min. The following concentration gradient method is used.

The ratio of the area of impurities is calculated using the following formula: Total of impurities (%) = total area of impurity peaks × 100
Sum of all peak areas

Synthesis SAM Classic (719.35 g) of crystalline ethanol solvate is added to 5.4 L of deionized water. The resulting slurry is stirred at ambient temperature for approximately 25 hours. Filter the slurry using nitrogen pressure. Wash the filter cake with 2.165 L of water. The filter cake is dried with nitrogen substitution while bubbling through a saturated aqueous solution of potassium acetate at ambient temperature while maintaining constant humidity. The relative humidity of nitrogen during filtration is 22.9% and the pressure is 15 PSI. The filter cake is dried until the water is measured at 8.5-11% by the KF analysis described herein. After approximately 112 hours, the KF is 8.85% and 666.20 g of SAM Classic hydrate is obtained.

Formulation Preferably, the SAM Classic hydrate of the invention is formulated into a unit dosage form prior to administration to a recipient patient. Preferably, the SAM Classic hydrate is formulated using a dry mixing process. SAM Classic hydrate alone is very poor in fluidity, so fluidity problems (powder agglomeration) during filling (leads to poor control over weight uniformity) and / or homogeneity problems after mixing However, the formulations described herein have acceptable mixing and homogeneity and are even stronger.

Formulation example

  Sieve partially pregelatinized starch using a 10 mesh sieve. Add pregelatinized starch to the tumble container. SAM Classic hydrate (API) is added to the tumble container and the API is laminated to the starch. Mix for 15 minutes at 13 rpm. The resulting mixture is passed through a Comill (sieve size: less than 610 μm). The resulting mixture is returned to the tumble container and mixed at 13 rpm for 30 minutes. Sieve starch flowable powder (5% silicon) using a 10 mesh sieve and add to the mixture in the tumble container. Mix for 15 minutes at 13 rpm. Fill into type 0 capsules. The filled capsules are refrigerated at 2-8 ° C. in a sealed foil bag.

Functional Demonstration The free base of SAM Classic is disclosed in WO 98/09625 (Example 87), the contents of which are incorporated herein by reference. In the “functional agonist B3 assay”, this free base material is “at least 30%... Isoproterenol response at a single dose of 50 mmol. ₅₀ values indicate <10 mM ... ". When screened against the B1 and B2 receptors in a functional assay, the compounds of the present invention show that receptor stimulation is significantly reduced or not observed in dose titration experiments.

Utility Diseases, disorders or conditions for which SAM Classic hydrate is useful for treatment include, but are not limited to type 2 diabetes and obesity. In general, human patients in need of treatment for obesity and / or type 2 diabetes have hypertension, high cholesterol, heart disease or diabetes with a body mass index (BMI) greater than 30 or a BMI of 27 or greater. It is patient suffering from.

Dose The specific dose to be administered is determined by the particular environment surrounding each situation. These circumstances include the route of administration (preferably oral), the recipient's medical history, the pathological condition or symptom being treated, the severity of the condition / symptom, and the age of the recipient. The recipient patient's physician will need to determine the therapeutic dose to be administered, taking into account the relevant environment. In general, an effective minimum daily dose is about 1 mg or more. Generally, an effective maximum daily dose is less than about 600 mg.

Combination therapy SAM Classic free base or a pharmacological salt thereof (preferably SAM Classic free hemisuccinate, more preferably SAM Classic hydrate) to treat a disease or condition for which the salt is useful For example, it may be used in combination with other agents used for the treatment of obesity and / or type 2 diabetes. Such other agents may be administered concomitantly or sequentially with the free base of SAM Classic (or their salts), by the route and in commonly used amounts. When a SAM Classic free base or a salt thereof is used simultaneously with one or more other agents, a pharmacological unit containing such an additional agent in addition to the SAM Classic free base (or a salt thereof) A dosage form is preferred. Accordingly, the pharmaceutical compositions of the present invention comprise one or more other active ingredients in addition to the SAM Classic free base (or salts thereof).

  A preferred combination therapy for the treatment of obesity is Meridia® (sibutramine or an active metabolite of sibutramine, such as desmethylsibutramine and di-desmethylsibutramine, preferably sibutramine hydrochloride monohydrate) or xenical (registered) Use of SAM Classic hydrate in combination with (trademark) (Oristat).

It is a typical XRD pattern of SAM Classic hydrate.

Claims (21)

  (S)-(3-pyridinecarboxamide, 6- [4- [2-[[3- (9H-carbazol-4-yloxy) -2-hydroxypropyl] amino] -2-methylpropyl] phenoxy])-hemi A crystalline nonstoichiometric hydrate of succinate, wherein the water content of the hydrate is 6-11% by weight when measured at 22 ± 5 ° C. and a relative humidity of 10-80%. Hydrate.   The hydrate according to claim 1, wherein the water content is 7.5 to 11%.   When an X-ray diffraction pattern is obtained using a copper radiation source (CuKα; λ = 1.54056 Angstrom) at 20-25 ° C. and 25-30% relative humidity (RH), 7.6 ± 2θ The hydrate according to claim 1 or 2, having a pattern including peaks at 0.1 and 8.8 ± 0.1 °.   4. The hydrate of claim 3, having an X-ray diffraction pattern further comprising peaks at 13.1 ± 0.1 and 15.5 ± 0.1 ° at 2θ.   X-ray diffraction further including peaks at 8.0 ± 0.1, 11.0 ± 0.1, 13.3 ± 0.1, 13.8 ± 0.1 and 15.3 ± 0.1 ° at 2θ. 5. A hydrate according to claim 4, having a pattern. Hydrate is 33% R.D. before data collection. H. A solid state ¹³ C nuclear magnetic resonance spectrum comprising peaks at chemical shifts of 59.8 ± 0.1, 111.4 ± 0.1 and 151.4 ± 0.1 ppm when equilibrated in 1. The hydrate according to 1. Solid state ¹³ further comprising peaks at chemical shifts of 99.2 ± 0.1, 102.4 ± 0.1, 134.9 ± 0.1, 146.9 ± 0.1 and 149.2 ± 0.1 ppm 7. A hydrate according to claim 6, having a C nuclear magnetic resonance spectrum.   The hydrate according to any one of claims 1 to 7, wherein the abundance of chemical impurities is less than 2% by weight.   The hydrate according to any one of claims 1 to 8, wherein the abundance of ethanol is 1% by weight or less.   (S)-(3-pyridinecarboxamide, 6- [4- [2-[[3- (9H-carbazol-4-yloxy) -2-hydroxypropyl] amino] -2-methylpropyl] phenoxy])-hemi A crystalline non-stoichiometric hydrate of succinate with an X-ray diffraction pattern of 20-25 ° C. and a relative humidity (RH) of 25-30%, a copper radiation source (CuKα; λ = 1. Hydrate with a pattern containing peaks at 7.6 ± 0.1 and 8.8 ± 0.1 ° at 2θ as obtained using 54056 angstroms).   11. The hydrate of claim 10, having an X-ray diffraction pattern further comprising peaks at 2θ at 13.1 ± 0.1 and 15.5 ± 0.1 °.   X-ray diffraction further including peaks at 8.0 ± 0.1, 11.0 ± 0.1, 13.3 ± 0.1, 13.8 ± 0.1 and 15.3 ± 0.1 ° at 2θ. The hydrate of claim 11 having a pattern. (S)-(3-pyridinecarboxamide, 6- [4- [2-[[3- (9H-carbazol-4-yloxy) -2-hydroxypropyl] amino] -2-methylpropyl] phenoxy])-hemi A crystalline non-stoichiometric hydrate of succinate salt, said hydrate being 33% R.D. before data collection. H. Hydration with solid state ¹³ C nuclear magnetic resonance spectra including peaks at chemical shifts of 59.8 ± 0.1, 111.4 ± 0.1 and 151.4 ± 0.1 ppm when equilibrated in object. Solid state ¹³ further comprising peaks at chemical shifts of 99.2 ± 0.1, 102.4 ± 0.1, 134.9 ± 0.1, 146.9 ± 0.1 and 149.2 ± 0.1 ppm 13. A hydrate according to claim 12, having a C nuclear magnetic resonance spectrum.   A pharmaceutical composition comprising an effective amount of the hydrate according to any one of claims 1 to 14 and a pharmacological carrier.   The pharmaceutical composition according to claim 15, comprising 1 to 600 mg of the hydrate.   A method of treating type 2 diabetes, wherein an effective amount of a hydrate according to any of claims 1 to 14 or a composition according to claim 15 or 16 is administered to a patient in need of treatment. A method involving that.   A method of treating obesity, comprising administering an effective amount of the hydrate according to any one of claims 1 to 14 or the composition according to claim 15 or 16 to a patient in need of treatment. Including methods.   The hydrate according to any of claims 1 to 14 or the composition according to claim 15 or 16 for use in a method of therapeutically treating the human body.   Use of the hydrate according to any one of claims 1 to 14 or the composition according to claim 15 or 16 for the manufacture of a medicament for the treatment of obesity or type 2 diabetes.   Use of the hydrate according to any one of claims 1 to 14 or the composition according to claim 15 or 16 for the manufacture of a medicament for the treatment of obesity.

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